Cyclosporine A가 혈관 반응도에 미치는 영향

Abstract

Recently introduced cyclosporine A, a fungal endecapeptide, is frequently used after organ trans- plantation and in certain autoimmune diseases due to its selective inhibition of T-cell related immune responses. Despite this advantage, serious side ef- fects such as nephrotoxicity and hypertension have limited its use. Nephrotoxicity was reported to occur due to the increased resistance in renal arteries resulting in ischemic damage and hypertension due to the inereased vascular contractility or decreased vascular relaxation. However, the exact psthophysiological mechanisms of these complications remain unclear. This study was planned to ascertain the effect of cyclosporine A on vascular reactivity and also its mechanism of action. By using the thoracic aortic segment of cyclosporine A treated rat, after contracting the aortic segment with norepinephrine, endothelium dependent relaxation by acetylcholine was compared with the control group which was treated with cremophor, the vehicle of cyclosporine A. The effect of indomethacin, superoxide dismutase, endothelin receptor A antagonist, L arginine on the altered endothelium dependent relaxation of the cyclosporine A treated rat was also evaluated by preincubating each drug and observing differ- ences in vascular relaxation by acetylcholine. Endo- thelium independent relaxation by sodium nitro- prusside and the vascular contractility by norepi- nephrine were compared between cyclosporine A treated and control group. Morphological changes in the endothelial cells and the smooth muscle were also evaluated by light & electron microscope after the cyclosporine A treatment. The results are as follow.: 1) The endothelium dependent relaxation by ace- tylcholine was decreased significantly in the cyclosporine A treated group compared with the cremophor treated group. 2) Suppression of endothelium dependent relaxa- tion in the cyclosporine A treated group was not reversed after the preincubation with indometha- cin, superoxide dismutase, and endothelin receptor A antagonist, 3) Suppressed endothelium dependent relaxation observed in the cyclosporine A treated group was recovered following preincubation with L arginine, the substrate of NO. 4) The endothelium independent relaxation by nitroprusside was also decreased in the cyclosporine A treated group compared with the cremo- phor treated group. 5) No significant changes in vascular contractility by norepinephrine were noted in the cyclospo- rine A-treated group. 6) Morphological changes after the cyclosporine A trestment were mainly observed in the vascular endothelial cells, cuboidal changes of the endotheli- al cells in the renal artery and appearance of cyto- plasmic vacuoles and phagolysosome within the en- dothelial cells, detachment of the endothelial cells from the basement membrane in the aorta. From the above results, it can be concluded that the main effect of cyclosporine A on the vascular reactivity is inhibition of endothelium dependent re- laxation and its principal mechanism of action seems to be the defect in the NO forming mecha- nism from the L arginine caused by cyclosporine A rather than the increased activity of the EDCF such as prostaglandin H thrornboxane A, or su- peroxide anion.